CN103130853A - Roxithromycin (ROX) crystal C type matter, preparation method thereof, medicine composition thereof and uses thereof - Google Patents
Roxithromycin (ROX) crystal C type matter, preparation method thereof, medicine composition thereof and uses thereof Download PDFInfo
- Publication number
- CN103130853A CN103130853A CN2012105518855A CN201210551885A CN103130853A CN 103130853 A CN103130853 A CN 103130853A CN 2012105518855 A CN2012105518855 A CN 2012105518855A CN 201210551885 A CN201210551885 A CN 201210551885A CN 103130853 A CN103130853 A CN 103130853A
- Authority
- CN
- China
- Prior art keywords
- crystal
- roxithromycin
- type
- sample
- value
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a novel crystal C type of roxithromycin (ROX) compound, wherein the novel crystal C type of the ROX compound is shown as a formula (I) and exists under the solid state. The invention relates to a preparation method of novel crystal C type samples, and relates to clinical therapeutic effects of various preparations and medicine compositions, the various preparations and medicine compositions are prepared and developed by using the crystal C type matter of ROX as active ingredients, wherein the various preparations and medicine compositions have the advantages of having the clinical therapeutic effects on diseases of respiratory tract, urinary tract, skin and soft tissue, era, nose, and throat (ENT), and the like, and the diseases are caused by sensitive bacteria (staphylococcus aureus, streptococcus pneumoniae, corynebacterium, listeriosis, catarrh Moraviabacteria, legionella and the like). The discovered crystal C type can affect absorption rate of solid medicine effective component inside an organism, and increase or decrease plasma concentration inside the organism, and therefore clinical preventive and therapeutic effects are achieved.
Description
Technical field
The present invention relates to find that Roxithromycin has three kinds of forms of crystal type A, crystal B-type, crystal C type under solid state; Relate to the preparation method who has invented three kinds of crystal form samples.
The different crystal forms material that the present invention relates to use Roxithromycin is developed the clinical treatment effect of making the most of the advantage in the diseases such as respiratory tract, urinary tract, skin and soft tissue due to the sensitive organisms such as bacterium, catarrh mora bacterium, legionella that streptococcus aureus, suis, coryneform bacteria, Lee department are made a mistake, department of eye infection of various pharmaceutical preparations and pharmaceutical composition as active fraction preparation.
The present invention relates to find that thereby crystal formation affects Roxithromycin solid pharmaceutical effective constituent absorption and speed, enhancing in vivo or reduced Plasma Concentration in organism and caused the curative effect difference between the effects of solid pharmaceutical in clinical disease control application.Wherein assimilation effect is crystal type A > crystal B-type > crystal C type, show that crystal type A is easier to by gastrointestinal absorption, thereby bring into play better clinical prevention effect.
Background technology
Roxithromycin, chemical name is the 9-[O-2-methoxy ethoxy)-methyl] oxime] erythromycin).
The Roxithromycin molecular structure is as shown in the formula (I):
In existing Chinese patent, majority is the formulation protection to Roxithromycin:
At Chinese patent CN1415305A(publication number) in put down in writing " the Roxithromycin slow-released pharmaceutics of Shenyang Pharmaceutical University's invention.Wherein, related to a kind of Roxithromycin slow-released pharmaceutics that can keep Plasma Concentration in 24 hours.
At Chinese patent CN1939273A(publication number) in put down in writing the Liu Fengming invention " contain Roxithromycin buccal lozenge and preparation method thereof.Wherein, related to a kind of buccal lozenge that comprises Roxithromycin and preparation method thereof.
At Chinese patent CN1709273A(publication number) in put down in writing " a kind of Roxithromycin soft capsule and preparation method thereof of Qin Yinlin invention.Wherein, related to a kind of Roxithromycin soft capsule and preparation method thereof.
At Chinese patent CN1336176A(publication number) in put down in writing " Roxoithromycin suppostory and the preparation method of Guangdong Qingfa Pharmaceutical Co., Ltd's invention.Wherein, a kind of Roxoithromycin suppostory and preparation method have been related to.
At Chinese patent CN1475221A(publication number) in put down in writing " the Roxithromycin spongaion of Bei's Pharmaceutical Co., Ltd, Guangzhou's invention.Wherein, related to a kind of Roxithromycin spongaion.
At Chinese patent CN1452975A(publication number) in put down in writing " a kind of roxithromycin injection of Bei's Pharmaceutical Co., Ltd, Guangzhou's invention invention.Wherein, related to a kind of hypertensive Roxithromycin dripping pill and preparation method thereof for the treatment of.
There are essential difference in point of penetration of the present invention and above-mentioned patent, be to start with from the research of Roxithromycin solid chemical material existence, by the screening polymorph technology, find on the bulk drug aspect of active constituents of medicine, find that Roxithromycin solid matter crystal formation exists kind and status flag, and crystal formation research is combined with Study on clinical pharmacodynamics, for the Roxithromycin solid pharmaceutical of finding, finding, exploitation has the optimal clinical curative effect provides the basic scientific research data; Simultaneously, also for from Roxithromycin solid crystal formation medicine material basic substance application country or international intellecture property invention patent protection, providing scientific basis.
Summary of the invention
The Roxithromycin molecular structure is as follows:
The present invention has found that the Roxithromycin compound has crystal type A, crystal B-type, three kinds of solid matter existence forms of crystal C type; Invented the preparation method who produces three kinds of crystal formation solid samples of Roxithromycin; Advantage clinical treatment effect curative effect that find to use various pharmaceutical preparations that Roxithromycin different crystal forms material develops as active fraction preparation and drug regimen too to bring into play in the diseases such as respiratory tract, urinary tract, skin and the soft tissue due to the sensitive organisms such as bacterium, catarrh mora bacterium, legionella, department of eye infection in streptococcus aureus, suis, coryneform bacteria, Lee department is different; Find that thereby crystal formation affects Plasma Concentration in Roxithromycin solid pharmaceutical effective constituent absorption rate, enhancing or minimizing organism in vivo and affects the curative effect effect of medicine in clinical.
One of the object of the invention: be to provide not three kinds of solid matter existences and describing mode containing Roxithromycin crystal type A, crystal B-type and the crystal C type of crystal water or other recrystallisation solvent.
Two of the object of the invention: the preparation method who is to provide three kinds of solid matter samples of Roxithromycin crystal type A, crystal B-type, crystal C type.
Three of the object of the invention: be to provide and contain the advantage clinical treatment difference between the effects that the pharmaceutical composition that uses Roxithromycin crystal-form substances (containing crystal type A or crystal B-type or crystal C type or by two kinds and three kinds of mixing crystal-form substances that crystal formation becomes to be grouped into) to manufacture out as the active constituents of medicine raw material is brought into play in all kinds of infection class diseases of control.
Four of the object of the invention: be to provide to use and contain the human body every day dosage scope of Roxithromycin crystal-form substances (containing crystal type A or crystal B-type or crystal C type or by two kinds and three kinds of mixing crystal-form substances that crystal formation becomes to be grouped into) as active constituents of medicine.
Five of the object of the invention: be to provide to use and contain Roxithromycin crystal-form substances (containing crystal type A or crystal B-type or crystal C type or by two kinds and three kinds of mixing crystal-form substances that crystal formation becomes to be grouped into) and manufacture out for the clinical various pharmaceutical preparations of various tablets, capsule, pill, injection, slowly-releasing or controlled release and pharmaceutical composition as the active constituents of medicine raw material.
Six of the object of the invention: be to provide absorption and Plasma Concentration variance data that three kinds of crystal form samples of Roxithromycin exist in vivo, crystal type A is than crystal B-type, crystal C type good absorption, can reach peak concentration at 1 hour, show that the crystal type A of Roxithromycin is easier to bring into play clinical efficacy effect preferably by gastrointestinal absorption.
Technical characterictic
1. crystal type A solid sample morphological specificity and the preparation method of Roxithromycin:
1.1 the crystal type A solid sample of the Roxithromycin the present invention relates to, its morphological specificity is that the chemical purity of sample and crystal formation purity all are greater than 95% and containing crystal water or other recrystallisation solvent composition, show as the rhombic system symmetry when using the Single Crystal X-ray diffraction structure to analyze, spacer is P2
12
12
1, the unit cell parameters value
α=β=γ=90 °, molecule number Z=4 in structure cell.Accompanying drawing 1 provides the molecule relative configuration figure of Roxithromycin crystal type A solid sample, and accompanying drawing 2 provides the molecule stereo structure sciagraph of Roxithromycin crystal type A solid sample, and accompanying drawing 3 provides the structure cell accumulation graph of the molecule of Roxithromycin crystal type A solid sample along the arrangement of b axle.Table 1 provides non-hydrogen atom coordinate parameters and the equivalent temperature factor values of Roxithromycin crystal type A solid sample molecule, table 2 provides the one-tenth key interatomic bond long value of Roxithromycin crystal type A solid sample molecule, and the molecule that table 3 provides Roxithromycin crystal type A solid sample becomes key interatomic bond angle value.
Non-hydrogen atom coordinate parameters and the equivalent temperature factor values of table 1 Roxithromycin crystal type A solid sample molecule
The one-tenth key interatomic bond long value of table 2 Roxithromycin crystal type A solid sample molecule
The molecule of table 3 Roxithromycin crystal type A solid sample become key interatomic bond angle value (°)
1.2 the Roxithromycin crystal type A solid substance the present invention relates to, its morphological specificity is that the chemical purity of sample and crystal formation purity all are greater than 95% and containing crystal water or other recrystallisation solvent composition, when using powder x-ray diffraction analysis to adopt CuK
αdiffraction peak position 2-Theta value during the radiation experiments condition (°) or the d value
diffraction peak relative intensity peak height value (Height%) or peak area value (Area%) have following expression.Table 4 provides the powder x-ray diffraction peak value of Roxithromycin crystal type A solid sample, and accompanying drawing 4 provides the x-ray diffractogram of powder spectrum of Roxithromycin crystal type A solid sample.
The powder x-ray diffraction peak value of table 4 Roxithromycin crystal type A solid sample
1.3 the Roxithromycin crystal type A solid sample the present invention relates to, its morphological specificity is 3572.7 when the KBr compressing tablet that uses infrared spectra is analyzed, 3526.9, 3462.0, 3279.5, 2981.5, 2970.0, 2938.7, 2881.1, 2829.0, 2788.7, 1743.4, 1735.5, 1634.6, 1465.6, 1457.9, 1406.7, 1386.6, 1375.9, 1344.8, 1328.7, 1287.7, 1242.3, 1168.3, 1128.6, 1112.4, 1095.4, 1073.9, 1051.6, 1028.1, 1012.0, 1003.9, 982.8, 958.2, 914.3, 892.0, 865.1, 847.1, 832.4, 803.5, 790.5, 768.8, 754.1, 724.8, 707.6, 698.0, 668.8, 659.3, 635.3, 616.9, 597.9, 573.0, 519.5, 488.4, 462.4cm
-1place has absorption peak to exist, wherein 3572.7,3526.9,3279.5,2981.5,1743.4,1465.6,1406.7,1386.6,1328.7,1287.7,1242.3,1112.4,1095.4,1073.9,1028.1,1003.9,832.4,803.5,790.5,768.8,754.1,724.8,707.6,668.8,597.9,573.0,519.5,488.4cm
-1peak is the characteristic absorbance peak position that presents Roxithromycin crystal type A solid sample.Accompanying drawing 5 provides Roxithromycin crystal type A solid sample infrared absorption spectrum.
1.4 the Roxithromycin crystal type A solid sample the present invention relates to, its morphological specificity is that melting point values while using melting point apparatus to carry out sample analysis is about 110 ~ 112 ° of C left and right.
1.5 prepare the method for Roxithromycin crystal type A material, first use the single solvent of methyl alcohol, ethanol, chloroform, acetone, ethyl acetate, propyl carbinol, Virahol, acetonitrile, tetrahydrofuran (THF), dioxane, ether, methylene dichloride, dioxane, DMF, n-propyl alcohol, DMSO, pyridine or 95% ethanol at ° C temperature of 15 ° of C ~ 80, the Roxithromycin sample to be dissolved fully and the recrystallization preparation technology under envrionment temperature 4 ° of C ~ 80 ° C, ambient moisture 10% ~ 75%, normal pressure or vacuum experiment conditions obtains the crystal type A solid substance of Roxithromycin.
Another method for preparing Roxithromycin crystal type A material, first use methyl alcohol, ethanol, chloroform, acetone, ethyl acetate, propyl carbinol, Virahol, acetonitrile, tetrahydrofuran (THF), dioxane, ether, methylene dichloride, dioxane, DMF, n-propyl alcohol, DMSO, any two or more solvents in pyridine or 95% ethanol different sorts solvent dissolve the Roxithromycin sample fully and through 4 ° of C ~ 80 ° C of envrionment temperature after different proportionings are mixed at ° C temperature of 15 ° of C ~ 80, ambient moisture 10% ~ 75%, recrystallization preparation technology under normal pressure or vacuum experiment condition obtains the crystal type A solid substance of Roxithromycin.
The problem that needs explanation: because the single organic solvent for the preparation of crystal type A Roxithromycin sample has 19 kinds, can hundreds of be arranged for the preparation of two kinds of crystal type A Roxithromycin sample or above solvent combination, every kind of organic solvent boiling point value is different, to Roxithromycin sample dissolution degree difference, cause the variate-values such as envrionment temperature, humidity, time, pressure of its experiment while under using the different solvents condition, preparing crystal type A Roxithromycin sample all there is some difference property and constant interval scope.
2. crystal B-type solid sample morphological specificity and the preparation method of Roxithromycin:
2.1 the Roxithromycin crystal B-type solid sample the present invention relates to, its morphological specificity is that the chemical purity of sample and crystal formation purity all are greater than 95% and containing crystal water or other recrystallisation solvent composition, when using powder x-ray diffraction analysis to adopt CuK
αdiffraction peak position 2-Theta value during the radiation experiments condition (°) or the d value
diffraction peak relative intensity peak height value (Height%) or peak area value (Area%) have following expression.Table 5 provides the powder x-ray diffraction peak value of Roxithromycin crystal B-type solid sample, and accompanying drawing 6 provides the x-ray diffractogram of powder spectrum of Roxithromycin crystal B-type solid sample.
The powder x-ray diffraction peak value of table 5 Roxithromycin crystal B-type solid sample
2.2 the Roxithromycin crystal B-type solid sample the present invention relates to, its morphological specificity is 3463.2 when the KBr compressing tablet that uses infrared spectra is analyzed, 2973.4, 2939.4, 2881.4, 2832.3, 2789.3, 1737.1, 1634.6, 1458.7, 1399.5, 1377.4, 1344.4, 1282.7, 1259.4, 1245.2, 1168.0, 1126.2, 1110.1, 1085.4, 1052.8, 1033.5, 1012.2, 983.9, 957.0, 914.7, 891.6, 864.6, 848.0, 838.0, 803.4, 790.1, 771.0, 751.7, 726.7, 709.7, 697.9, 662.1, 636.5, 616.6, 581.6, 558.5, 496.5, 460.5cm
-1place has absorption peak to exist, wherein 1399.5,1245.2,1110.1,1085.4,1012.2,838.0,771.0,726.7,709.7,662.1,581.6,558.5,496.5cm
-1peak is the characteristic absorbance peak position that presents Roxithromycin crystal B-type solid sample.Accompanying drawing 7 provides Roxithromycin crystal B-type solid sample infrared absorption spectrum.
2.3 the Roxithromycin crystal B-type solid sample the present invention relates to, its morphological specificity is that melting point values while using melting point apparatus to carry out sample analysis is about 102 ~ 104 ° of C left and right.
2.4. prepare the method for Roxithromycin crystal B-type material, first use the single solvent of methyl alcohol, ethanol, chloroform, acetone, ethyl acetate, propyl carbinol, Virahol, acetonitrile, tetrahydrofuran (THF), dioxane, ether, methylene dichloride, dioxane, DMF, n-propyl alcohol, DMSO, pyridine or 95% ethanol at ° C temperature of 15 ° of C ~ 80, the Roxithromycin sample to be dissolved fully and the recrystallization preparation technology under envrionment temperature 4 ° of C ~ 80 ° C, ambient moisture 10% ~ 75%, normal pressure or vacuum experiment conditions obtains the crystal B-type solid matter of Roxithromycin.
Another method for preparing Roxithromycin crystal B-type material, first use methyl alcohol, ethanol, chloroform, acetone, ethyl acetate, propyl carbinol, Virahol, acetonitrile, tetrahydrofuran (THF), dioxane, ether, methylene dichloride, dioxane, DMF, n-propyl alcohol, DMSO, any two or more in pyridine or 95% ethanol different sorts solvent dissolve the Roxithromycin sample fully and through 4 ° of C ~ 80 ° C of envrionment temperature after different proportionings are mixed at ° C temperature of 15 ° of C ~ 80, ambient moisture 10% ~ 75%, recrystallization preparation technology under normal pressure or vacuum experiment condition obtains the crystal B-type solid matter of Roxithromycin.
The problem that needs explanation: because the single organic solvent for the preparation of crystal type A Roxithromycin sample has 19 kinds, can hundreds of be arranged for the preparation of two kinds of crystal B-type Roxithromycin sample or above solvent combination, every kind of organic solvent boiling point value is different, to Roxithromycin sample dissolution degree difference, cause the variate-values such as envrionment temperature, humidity, time, pressure of its experiment while under using the different solvents condition, preparing crystal B-type Roxithromycin sample all there is some difference property and constant interval scope
3. crystal C type solid sample morphological specificity and the preparation method of Roxithromycin:
3.1 the Roxithromycin crystal C type solid sample the present invention relates to, its morphological specificity is that the chemical purity of sample and crystal formation purity all are greater than 95% and containing crystal water or other recrystallisation solvent composition, when using powder x-ray diffraction analysis to adopt CuK
αdiffraction peak position 2-Theta value during the radiation experiments condition (°) or the d value
diffraction peak relative intensity peak height value (Height%) or peak area value (Area%) have following expression.Table 6 provides the powder x-ray diffraction peak value of Roxithromycin crystal C type solid sample, and accompanying drawing 8 provides the x-ray diffractogram of powder spectrum of Roxithromycin crystal C type solid sample.
The powder x-ray diffraction peak value of table 6 Roxithromycin crystal C type solid sample
3.2 the Roxithromycin crystal C type solid sample the present invention relates to, its morphological specificity is 3466.8 when the KBr compressing tablet that uses infrared spectra is analyzed, 2972.8, 2937.9, 2880.4, 2830.5, 2787.0, 1736.2, 1631.3, 1458.7, 1402.7, 1378.4, 1344.9, 1282.0, 1246.7, 1167.7, 1127.7, 1108.2, 1087.3, 1053.1, 1033.9, 1013.0, 983.8, 957.3, 914.8, 892.8, 864.5, 836.4, 803.6, 789.1, 769.8, 751.0, 727.2, 698.0, 680.9, 636.4, 617.1, 589.5, 494.1, 461.1cm
-1place has absorption peak to exist, wherein 1402.7,1378.4,1246.7,1108.2,1087.3,1013.0,836.4,769.8,727.2,680.9,589.5,494.1cm
-1peak is the characteristic absorbance peak position that presents Roxithromycin crystal C type solid sample.Accompanying drawing 9 provides Roxithromycin crystal C type solid sample infrared absorption spectrum.
3.3 the present invention relates to Roxithromycin crystal C type solid sample, its morphological specificity is that melting point values when using melting point apparatus to carry out sample analysis is about 71 ~ 76 ° of C left and right.
3.4 prepare the method for Roxithromycin crystal C type material, be to use Roxithromycin crystal B-type sample as raw materials, adopt thermostatic heating method to prepare the crystal C type solid matter of Roxithromycin under 50 ~ 65 ° of C conditions after 10 ~ 30min time turns crystalline substance.
Another method for preparing Roxithromycin crystal C type material, first to use methyl alcohol, ethanol, chloroform, acetone, ethyl acetate, propyl carbinol, Virahol, acetonitrile, tetrahydrofuran (THF), dioxane, ether, methylene dichloride, dioxane, DMF, n-propyl alcohol, DMSO, pyridine or 95% ethanol single solvent dissolve the Roxithromycin sample fully or use methyl alcohol, ethanol, chloroform, acetone, ethyl acetate, propyl carbinol, Virahol, acetonitrile, tetrahydrofuran (THF), dioxane, ether, methylene dichloride, dioxane, DMF, n-propyl alcohol, DMSO, any two or more in pyridine or 95% ethanol different sorts solvent dissolve the Roxithromycin sample fully the crystal C type solid matter that adopts again cold spray or thermal spray or thermal spray method to prepare fast Roxithromycin after different proportionings are mixed at ° C temperature of 15 ° of C ~ 80.
The problem that needs explanation: hundreds of is arranged because the single organic solvent that can be used for preparing crystal C type Roxithromycin sample has 19 kinds, two or more solvent combination, every kind of organic solvent boiling point value is different, to Roxithromycin sample dissolution degree difference, cause the variate-values such as envrionment temperature, humidity, time of its experiment while under using the different solvents condition, preparing crystal C type Roxithromycin sample all there is some difference property and constant interval scope.
4. the crystal formation composition of Roxithromycin, dosage and pharmaceutical preparations composition feature:
4.1 the use the present invention relates to the various pharmaceutical compositions that manufacture out as active constituents of medicine of the crystal form samples of Roxithromycin, it is characterized in that containing Roxithromycin crystal type A composition or contain Roxithromycin crystal B-type composition or contain Roxithromycin crystal C type composition or contain Roxithromycin mixing crystal formation composition.
4.2 the use the present invention relates to the crystal form samples of Roxithromycin manufacture out dosage every day of various pharmaceutical compositions as active constituents of medicine, it is characterized in that the administration every day experience scope of the Roxithromycin crystal form samples that contains is 20 ~ 1000mg.
4.3 the use the present invention relates to the pharmaceutical preparation of Roxithromycin crystal formation solid matter as active constituents of medicine exploitation preparation, it is characterized in that using Roxithromycin crystal formation composition in pharmaceutical composition, used Roxithromycin crystal formation composition dosage scope every day, used and contained one or more pharmaceutical excipients and manufacture out for clinical tablet, capsule, pill, injection, slowly-releasing or controlled-release pharmaceutical formulation type.
The problem that needs explanation: the crystal formation Roxithromycin pharmaceutical composition the present invention relates to has many factor impacts on the dosage of effective constituent, for example: the difference that causes dosage every day for the purposes of preventing and treat is different; Ill character is different from ill severity and cause the different of dosage every day; The difference of Gender, age, body surface area, route of administration, administration number of times, therapeutic purpose are different and cause the difference of dosage every day; In addition, the absorption existed between crystal form samples and Plasma Concentration are not equal, and also causing the present invention is the 0.01-150mg/kg body weight in appropriate dose scope every day of using crystal formation Roxithromycin composition, is preferably the 1-100mg/kg body weight.Should formulate different crystal formation Roxithromycin effective constituent total dose schemes from treatment different situations demand according to actual prevention during use, and can be divided into repeatedly or the single administration mode completes.
5. the pharmacodynamic profile of different crystal forms Roxithromycin:
5.1 absorption and Plasma Concentration difference that the different crystal forms Roxithromycin solid matter the present invention relates to exists in vivo, it is characterized in that biological test proof crystal type A, crystal B-type and crystal C type solid sample have significant absorption and Plasma Concentration difference in vivo, wherein crystal type A is easier to by gastrointestinal absorption than crystal B-type, crystal C type, brings into play larger drug action.Figure 10 provides the determination of plasma concentration result in the rat body after crystal type A, crystal B-type and crystal C type Roxithromycin sample oral absorption.
The clinical treatment advantage function brought into play in the diseases such as respiratory tract, urinary tract, skin and soft tissue due to bacterium, catarrh mora bacterium, legionella etc., department of eye infection 5.2. the Roxithromycin crystal formation preparation the present invention relates to is made a mistake in control streptococcus aureus, suis, coryneform bacteria, Lee department, thus it is characterized in that crystal formation has changed absorption rate in vivo of effective ingredient, the Plasma Concentration strengthened in organism reaches the preventive and therapeutic effect of raising medicine in clinical.
The accompanying drawing explanation
The molecule relative configuration figure of Fig. 1 Roxithromycin crystal type A solid sample,
The molecule stereo structure sciagraph of Fig. 2 Roxithromycin crystal type A solid sample,
The structure cell accumulation graph that the molecule of Fig. 3 Roxithromycin crystal type A solid sample is arranged along the b axle.
The x-ray diffractogram of powder spectrum of Fig. 4 Roxithromycin crystal type A solid sample.
Fig. 5 Roxithromycin crystal type A solid sample infrared absorption spectrum.
The x-ray diffractogram of powder spectrum of Fig. 6 Roxithromycin crystal B-type solid sample
Fig. 7 Roxithromycin crystal B-type solid sample infrared absorption spectrum.
The x-ray diffractogram of powder spectrum of Fig. 8 Roxithromycin crystal C type solid sample.
Fig. 9 Roxithromycin crystal C type solid sample infrared absorption spectrum.
Determination of plasma concentration after tri-kinds of crystal formation Roxithromycin sample oral absorption of Figure 10 in the rat body
Embodiment
The following examples are used for further illustrating the present invention, but this and do not mean that any limitation of the invention.Embodiment 1
The preparation method 1 of crystal type A Roxithromycin sample:
The preparation method of crystal type A Roxithromycin sample, it is characterized in that first using benzene solvent under 15 ~ 25 ° of C normal temperature states, the Roxithromycin sample to be dissolved fully, under the vacuum condition that the recycling Rotary Evaporators is 40 ° of C in temperature, solvent is steamed fast and prepares the crystal type A Roxithromycin solid matter obtained.
The preparation method 2 of crystal type A Roxithromycin sample:
The preparation method of crystal type A Roxithromycin sample, it is characterized in that first using petroleum ether solvent under 15 ~ 25 ° of C normal temperature states, the Roxithromycin sample to be dissolved fully, under the vacuum condition that the recycling Rotary Evaporators is 40 ° of C in temperature, solvent is steamed fast and prepares the crystal type A Roxithromycin solid matter obtained.
The preparation method 1 of crystal B-type Roxithromycin sample:
The preparation method of crystal B-type Roxithromycin sample, it is characterized in that first using alcohol solvent under 15 ~ 25 ° of C normal temperature states, the Roxithromycin sample to be dissolved fully, under the vacuum condition that the recycling Rotary Evaporators is 40 ° of C in temperature, solvent is steamed fast and prepares the crystal B-type Roxithromycin solid matter obtained.
The preparation method 2 of crystal B-type Roxithromycin sample:
The preparation method of crystal B-type Roxithromycin sample, it is characterized in that first using acetone solvent under 15 ~ 25 ° of C normal temperature states, the Roxithromycin sample to be dissolved fully, under the vacuum condition that the recycling Rotary Evaporators is 40 ° of C in temperature, solvent is steamed fast and prepares the crystal B-type Roxithromycin solid matter obtained.
The preparation method 1 of crystal C type Roxithromycin sample:
The preparation method of crystal C type Roxithromycin sample, is characterized in that first using cyclohexane solvent under 15 ~ 25 ° of C normal temperature states, the Roxithromycin sample to be dissolved fully, then adopt the cold spray method to prepare fast crystal C type Roxithromycin solid matter.
Three kinds of crystal formation Roxithromycin solid pharmaceutical Absorption Characteristics and Plasma Concentration feature in the rat body:
Laboratory animal: the SD rat, male, body weight: 210 ± 10g.Be purchased from Beijing dimension tonneau China experimental technique company limited.
Experimental technique: respectively by Roxithromycin crystal type A, crystal B-type, crystal C type.Be mixed with the 20mg/ml suspension with suitable solution (physiological saline).The conventional raising condition of rat is raised, and freely drinks water, and after fasting 12h, by the 200mg/kg gavage, gives medicine.After administration 0.18,0.33,0.67,1,1.5,2,3,4,6(h).Eye socket is got the about 0.5ml of blood, the centrifugal 30min of 4500rpm.Get 200 μ l blood plasma, add ether 1ml, vortex oscillation 1min, the centrifugal 15min of 4500rpm, get ether layer 800 μ l; Add again 100 μ l4mmol/L H
3pO
4, vortex oscillation 1min, the centrifugal 15min of 4500rpm; Get 100 μ l lower floor waters and carry out the HPLC detection.
The HPLC condition: detection system is the Aligent1100 highly effective liquid phase chromatographic system, chromatographic column is AligentZorbax Eclipse XDB-C18 (150 * 4.6mm, 5 μ m), moving phase is acetonitrile: phosphate buffered saline buffer (PH6.7)=45:55, sample size is 20 μ l, flow velocity is 1ml/min, and the detection wavelength is 210nm, and column temperature is 27 ℃
Detected result shows, there is notable difference in three kinds of crystal formations of Roxithromycin in the absorption of rat gastrointestinal tract.Wherein the more brilliant B of brilliant A, brilliant C good absorption, can reach peak concentration at 1 hour.
The dosage 1 of crystal formation Roxithromycin medicinal composition:
The pharmaceutical composition that uses crystal formation Roxithromycin sample to manufacture as active constituents of medicine, it is characterized in that using the activeconstituents of crystal type A Roxithromycin as medicine, every day, dosage was 60mg, can be prepared into respectively 3 times/each 1 20mg conventional tablet every day, every day 2 times/each 1 30mg conventional tablet or every day 1 time/each 1 60mg slow control formula tablet type.
The dosage 2 of crystal formation Roxithromycin medicinal composition:
The pharmaceutical composition that uses crystal formation Roxithromycin sample to manufacture as active constituents of medicine, it is characterized in that using the activeconstituents of mixed crystal Roxithromycin sample as medicine, wherein crystal type A accounts for more than 50% of Roxithromycin composition total amount, every day, dosage was 90mg, can be prepared into 3 times/each 1 30mg conventional tablet every day, every day 2 times/each 1 45mg conventional tablet or every day 1 time/each 1 90mg slow control formula tablet type.
The preparation method 1 of the crystal type A medicinal composition solid dosage-tablet of Roxithromycin:
A kind of crystal type A solid substance that contains as described in claim 1 Roxithromycin drug regimen method for preparing tablet thereof as effective constituent that used, the crystal type A solid sample that it is characterized in that using Roxithromycin as active constituents of medicine, use several vehicle as the adjunct ingredient for preparing the medicinal composition tablet, proportioning is made the tablet samples of every crystal type A solid pharmaceutical composition 20～100mg that contains Roxithromycin according to a certain percentage, and table 7 provides the formula rate of conventional tablet:
Bulk drug and the accessory formula of the crystal type A solid medicinal composition tablet of table 7 Roxithromycin
The method that the crystal type A solid substance of the Roxithromycin of some amount and vehicle auxiliary material is prepared into to the various dose tablet is that several vehicle auxiliary materials are evenly mixed with bulk drug, add 1% sodium cellulose glycolate solution to make in right amount soft material, the granulation of sieving, wet grain is dried and is sieved whole, adds Magnesium Stearate and talcum powder mix rear compressing tablet and get final product.
The preparation method 2 of the A crystal formation medicinal composition solid dosage-capsule of Roxithromycin:
A kind of crystal type A solid sample that contains as described in claim 1 Roxithromycin drug regimen capsule preparations preparation method as effective constituent that used, the crystal type A solid sample that it is characterized in that using Roxithromycin as active constituents of medicine, use several vehicle as the adjunct ingredient for preparing the medicinal composition tablet, proportioning is made the capsule preparations of the crystal type A pharmaceutical cpd 20～100mg that contains Roxithromycin in every capsules according to a certain percentage, and table 8 provides the formula rate of conventional capsule preparation:
Bulk drug and the accessory formula of the A crystal formation solid medicinal composition capsule preparations of table 8 Roxithromycin
By the crystal type A solid substance of the Roxithromycin of some amount, with the method that the vehicle auxiliary material is prepared into capsule preparations, be: several vehicle auxiliary materials are mixed with the crystal type A solid material medicine of Roxithromycin, add 1% sodium cellulose glycolate solution appropriate, make wet grain and dry the whole grain that sieves, add Magnesium Stearate to mix, insert capsule and make; Or do not use granulation step, and directly the crystal type A solid material medicine of Roxithromycin is mixed with several vehicle auxiliary materials, after sieving, directly incapsulate and make.
Claims (11)
1. Roxithromycin crystal C type solid matter, is characterized in that, its chemical purity and crystal formation purity all are greater than 95% and containing crystal water or other recrystallisation solvent composition, when using powder x-ray diffraction analysis to adopt CuK
αdiffraction peak position 2-Theta value during the radiation experiments condition (°) or the d value
diffraction peak relative intensity peak height value (Height%) or peak area value (Area%) have following expression:
2. according to the Roxithromycin crystal C type solid matter of claim 1, it is characterized in that, when using infrared spectra to be analyzed 3466.8, 2972.8, 2937.9, 2880.4, 2830.5, 2787.0, 1736.2, 1631.3, 1458.7, 1402.7, 1378.4, 1344.9, 1282.0, 1246.7, 1167.7, 1127.7, 1108.2, 1087.3, 1053.1, 1033.9, 1013.0, 983.8, 957.3, 914.8, 892.8, 864.5, 836.4, 803.6, 789.1, 769.8, 751.0, 727.2, 698.0, 680.9, 636.4, 617.1, 589.5, 494.1, 461.1cm
-1place has absorption peak to exist, wherein 1402.7,1378.4,1246.7,1108.2,1087.3,1013.0,836.4,769.8,727.2,680.9,589.5,494.1cm
-1peak is to present the receipts peak position that Roxithromycin crystal C type solid matter feature is inhaled.
3. the method for preparing the crystal C type of Roxithromycin described in claim 1 material, it is characterized in that, be to use Roxithromycin crystal B-type sample as raw materials, adopt thermostatic heating method to prepare the crystal C type solid matter of Roxithromycin under 50 ~ 65 ° of C conditions after 10 ~ 30min time turns crystalline substance; Described Roxithromycin crystal B-type, when using powder x-ray diffraction analysis to adopt CuK
αdiffraction peak position 2-Theta value during the radiation experiments condition (°) or the d value
diffraction peak relative intensity peak height value (Height%) or peak area value (Area%) have following expression:
4. the method for preparing the described Roxithromycin crystal C type of claim 1 material, it is characterized in that, first to use methyl alcohol, ethanol, chloroform, acetone, ethyl acetate, propyl carbinol, Virahol, acetonitrile, tetrahydrofuran (THF), dioxane, ether, methylene dichloride, dioxane, DMF, n-propyl alcohol, DMSO, pyridine or 95% ethanol single solvent dissolve the Roxithromycin sample fully or use methyl alcohol, ethanol, chloroform, acetone, ethyl acetate, propyl carbinol, Virahol, acetonitrile, tetrahydrofuran (THF), dioxane, ether, methylene dichloride, dioxane, DMF, n-propyl alcohol, DMSO, any two or more in pyridine or 95% ethanol different sorts solvent dissolve the Roxithromycin sample fully the crystal C type solid matter that adopts again cold spray or thermal spray or thermal spray method to prepare fast Roxithromycin after different proportionings are mixed at ° C temperature of 15 ° of C ~ 80.
5. a Roxithromycin mixing crystal formation solid matter, is characterized in that, contains the mixing crystal formation solid sample that Roxithromycin crystal C type composition mixes in any proportion with Roxithromycin crystal type A and/or crystal B-type as described in claim 1; Wherein said Roxithromycin crystal type A shows as the rhombic system symmetry when using the Single Crystal X-ray diffraction structure to analyze, and spacer is P2
12
12
1, the unit cell parameters value
α=β=γ=90 °, molecule number Z=4 in structure cell; Described Roxithromycin crystal B-type, when using powder x-ray diffraction analysis to adopt CuK
αdiffraction peak position 2-Theta value during the radiation experiments condition (°) or the d value
diffraction peak relative intensity peak height value (Height%) or peak area value (Area%) have following expression:
6. a pharmaceutical composition, the crystal-form substances that contains Roxithromycin, as active constituents of medicine, is characterized in that, contains Roxithromycin crystal C type composition as claimed in claim 1 or contains Roxithromycin mixing crystal formation composition as described in claim 5.
7. according to the pharmaceutical composition of claim 6, it is characterized in that, the Roxithromycin crystal formation becomes divided dose in 20 ~ 1000mg scope.
8. according to the pharmaceutical composition of claim 6, it is characterized in that, described pharmaceutical composition is selected from tablet, capsule, pill, injection, slowly-releasing or controlled-release pharmaceutical formulation.
9. the application of Roxithromycin crystal C type solid matter claimed in claim 1 in preparing anti-infectives.
10. the application of Roxithromycin mixing crystal formation solid matter in preparing anti-infectives of claim 5.
11. according to arbitrary described application in claim 9-10, it is characterized in that, described infection is by being selected from streptococcus aureus, suis, coryneform bacteria, Lee department the bacterial of bacterium, catarrh mora bacterium or legionella of making a mistake.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210551885.5A CN103130853B (en) | 2008-10-06 | 2008-10-06 | Roxithromycin (ROX) crystal C type matter, preparation method thereof, medicine composition thereof and uses thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210551885.5A CN103130853B (en) | 2008-10-06 | 2008-10-06 | Roxithromycin (ROX) crystal C type matter, preparation method thereof, medicine composition thereof and uses thereof |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200810223650.7A Division CN101712707B (en) | 2008-10-06 | 2008-10-06 | Three crystal-form substances of roxithromycin, preparation method, pharmaceutical composition and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103130853A true CN103130853A (en) | 2013-06-05 |
| CN103130853B CN103130853B (en) | 2015-06-24 |
Family
ID=48491350
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210551885.5A Active CN103130853B (en) | 2008-10-06 | 2008-10-06 | Roxithromycin (ROX) crystal C type matter, preparation method thereof, medicine composition thereof and uses thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103130853B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104163840A (en) * | 2013-08-30 | 2014-11-26 | 郑州后羿制药有限公司 | Roxithromycin refining method |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0985680A1 (en) * | 1998-09-10 | 2000-03-15 | Hovione Inter Ltd. | A process for the purification of roxithromycin |
| EP1435359A1 (en) * | 2002-12-31 | 2004-07-07 | Alembic Limited | A process for the purification of roxithromycin |
-
2008
- 2008-10-06 CN CN201210551885.5A patent/CN103130853B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0985680A1 (en) * | 1998-09-10 | 2000-03-15 | Hovione Inter Ltd. | A process for the purification of roxithromycin |
| EP1435359A1 (en) * | 2002-12-31 | 2004-07-07 | Alembic Limited | A process for the purification of roxithromycin |
Non-Patent Citations (1)
| Title |
|---|
| 闫峰等: "罗红霉素合成工艺的改进", 《河北化工》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104163840A (en) * | 2013-08-30 | 2014-11-26 | 郑州后羿制药有限公司 | Roxithromycin refining method |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103130853B (en) | 2015-06-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101712707B (en) | Three crystal-form substances of roxithromycin, preparation method, pharmaceutical composition and application thereof | |
| US8574633B2 (en) | Huperzia serrata (Thunb.) Trev. composition comprising compounded Huperzine A and Huperzine B and methods for preparing it | |
| TW201247680A (en) | Amorphous N-benzoyl-staurosporine, processes for the preparation, and use thereof | |
| CN112745323B (en) | Citric acid alidenafil crystal form H and preparation method and application thereof | |
| CN104844600B (en) | A kind of tadanafil compound, and combinations thereof | |
| CN104447904B (en) | Stable gastrodine crystal that a kind of oral administration biaavailability is high and preparation method thereof, preparation and application | |
| CN103833712A (en) | Nicousamide compound crystal form II, preparation method, pharmaceutical composition and application thereof | |
| CN110022901A (en) | Pharmaceutical composition containing celecoxib | |
| CN103130853B (en) | Roxithromycin (ROX) crystal C type matter, preparation method thereof, medicine composition thereof and uses thereof | |
| CN109232293A (en) | Fragrant happy amine crystalline substance G type, preparation method and its composition and purposes | |
| CN101899041B (en) | Superior medicinal crystal-form solid substance of puerarin as well as preparation method and application thereof | |
| CN101544596B (en) | Preferred crystal-form substance of nitrendipine and preparation method, pharmaceutical composition and application thereof | |
| CN109232297A (en) | Fragrant happy amine crystal B-type, preparation method and its composition and purposes | |
| CN101550127B (en) | Two crystal substances of bicycle-ethanol, preparation method, pharmaceutical composition and application thereof | |
| CN101906101B (en) | Rotundine crystal B-type solid matter and preparation method as well as applications | |
| CN107200719B (en) | A kind of crystalline substance VII type substance of 990207-22-1, its preparation method and its pharmaceutical composition and purposes | |
| CN113214208A (en) | Hesperetin and isonicotinamide eutectic crystal, preparation method, composition and application thereof | |
| CN107200720B (en) | A kind of brilliant II type substance, its preparation method and its pharmaceutical composition and purposes | |
| CN109721557A (en) | Letrozole crystalline substance II type solid matter and preparation method and its pharmaceutical composition and purposes | |
| CN101899053B (en) | C crystal form solid matter of bergenin and preparation method and application thereof | |
| CN105384730A (en) | Empagliflozin crystal forms, preparation methods and uses thereof, and pharmaceutical composition | |
| CN104098583B (en) | Podophyllotoxin crystalline substance X-type material and preparation method and its pharmaceutical composition and purposes | |
| CN104098567B (en) | Diprophylline crystalline substance II types material and preparation method and its pharmaceutical composition and purposes | |
| KR20080030835A (en) | Pharmaceutical composition | |
| JPH04159225A (en) | Acetylcholine esterase inhibitor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |